Project Summary/Abstract: Chiari-type I malformation (CM1) is a developmental disorder estimated to affect 215,000 Americans. It is characterized by caudal herniation of the cerebellar tonsils below the foramen magnum and is frequently associated with syringomyelia (SM). In Cavalier King Charles Spaniels (CKCS), like people, Chiari-like malformations result in a brain and skull mismatch that produces a relatively small caudal fossa with crowding of the foramen magnum, and stenosis of the cranial venous sinuses and skull foramina. These changes conspire to produce turbulent flow of cerebrospinal fluid (CSF) and development of SM within the spinal cord. The CMSM complex in CKCS causes severe neuropathic pain mainly localized to the head and neck region manifesting as phantom scratching (scratching of the head and neck without making skin contact), sensitivity to touch, and screaming in pain. Similarly, clinical presentation of CM1 in humans is dominated by manifestations of neuropathic pain including occipital and upper cervical pain, and burning sensations of the upper extremities. A genetic basis for the human and canine condition have been inferred, however, many causes remain unknown. We propose that CMSM in CKCS is a model of CM1 in humans and that genetic discovery in this breed will have relevance for the human condition. In this project, we will leverage the genetic homogeneity of dog breeds to identify novel genetic variants associated with CMSM. These variants, and the pathways that they highlight, can then be investigated in humans with CM1. Our laboratory has developed clinical metrology tools to quantify the clinical phenotype and has extensive experience quantifying the morphological characteristics of CMSM in CKCS on MRI. In collaboration with Dr. Trudy Mackay's genetics laboratory, we will perform association mapping to identify variants using both case- control and quantitative trait study design. The primary purpose of this study is to identify loci associated with CMSM in CKCS but a preliminary examination of these loci for causative mutations will be performed. We propose to use both categorical and continuous measures of severity of CMSM based on morphologic MRI findings, as well as measures of neuropathic pain signs including owner-reported questionnaire data, and neurological examination findings. We hypothesize that quantitative trait loci (QTL) associated with CMSM in CKCS can be identified using a genome-wide association study and quantitative phenotypes. At the completion of this study, we will have uncovered novel loci associated with CMSM morphological changes and/or neuropathic pain that will be investigated for genetic variants associated with the traits. This work will pave the road for collaborative studies on the genetic basis of CM1 and associated neuropathic pain in humans.